Cancer is a disease in which growth stimulatory pathways are excessively active. Considerable experimental evidence implicates Ras proteins as essential components of growth stimulatory signal transduction pathways. Moreover, oncogenic forms of Ras are expressed in a variety of human cancers with a strikingly high prevalence (>90%) in pancreatic cancer. The long term objective of this research project is to define the precise role that oncogenic Ras plays in tumorigenesis. The combined efforts of many groups, including our own, have led to the identification of multiple effector pathways that are controlled by Ras. The goal of the studies proposed in this application is to characterize the cellular responses that are triggered by Ras-dependent effector pathways, and to assess the relevance of these responses to tumor initiation and progression. Our specific aims are as follows:[unreadable] 1. To identify effector pathways that couple the oncogenic activation of Ras to the metastatic phenotype.[unreadable] 2. To define the mechanisms by which Ras controls tumor-stroma interactions.[unreadable] 3. To delineate the function of Ras in pancreatic tumorigenesis.[unreadable] [unreadable] Collectively, the studies to be pursued within the framework of this proposal will advance our mechanistic understanding of growth control perturbation that are critical for oncogenic transformation and, as such, may lead to the identification of new modalities for therapeutic intervention.[unreadable] [unreadable] [unreadable] NEW AIMS [unreadable] 1 The elucidation of cross-talk mechanisms between Ras and Rho GTPases.[unreadable] 2 The identification of a novel mediator of Ras-induced tumorigenesis.[unreadable] 3 The establishment of a unique cell culture system for studying the role of oncogenic Ras in the initiation of pancreatic cancer.[unreadable] 4 The discovery of a new modality for regulating the signaling activity of Ras.[unreadable]